Increased iNOS protein and mRNA expression was found in ammonia-treated see more cultured rat astrocytes6, 20 and in brains of portocaval-shunted rats in vivo.21 However, iNOS mRNA expression was significantly reduced by approximately 50%

in ammonia (5 mmol/L, 6 hours)-treated microglia. As for control, lipopolysaccharide (LPS, 1 ng/mL, 6 hours) strongly increased iNOS mRNA expression (Supporting Information Fig. 1A). In addition, NH4Cl (5 mmol/L) exposure for 20 hours had no effect on iNOS protein expression as detected by immunofluorescence (data not shown). Activated microglia can express cyclooxygenase-2 (COX-2) and can be a powerful source of proinflammatory prostanoids, such as PGE2. However, NH4Cl (5 mmol/L) had no significant effect on COX-2 mRNA expression in microglia and astrocytes (Supporting Information Fig. 1B) and

even lowered the PGE2 and 6-keto prostaglandin F1α (PGF1α) content of microglial supernatants after 6 hours and 20 hours of ammonia exposure (Fig. 4B). On the other hand, and in contrast to microglia, NH4Cl (5 mmol/L) stimulated the release of PGE2 and 6-keto PGF1α from cultured astrocytes (Fig. 4A). LPS treatment (1 ng/mL, 6 hours or 20 hours), which served as a positive control, increased PGE2 and 6-keto PGF1α release from both RXDX-106 cell line cultured microglia and astrocytes (Fig. 4A,B). Extracellular glutamate can promote neuroinflammation by overactivation of N-methyl-D-aspartate receptors.22 In order to analyze the effect of ammonia on glutamate release, cultured microglia and astrocytes were incubated with NH4Cl (5 mmol/L) for 6 hours and 20 hours, and the glutamate content was measured in the supernatant. As shown in Supporting Information Fig. 2, no increase in extracellular glutamate was detected in the supernatant of cultured microglia exposed to NH4Cl (5 mmol/L) for 6 hours or 20 hours, whereas ammonia triggered glutamate release from cultured astrocytes as described recently.5 Activated microglia can promote neuroinflammation through the release of proinflammatory cytokines,23

which may play a role in the pathobiology of HE.1, 10, 11, 24 As shown in Fig. 5, treatment of cultured microglia or astrocytes with NH4Cl did not significantly change tumor necrosis factor α (TNF-α), Isotretinoin interleukin (IL)-1α, or IL-6 mRNA expression. Interleukin-1β mRNA expression was reduced by NH4Cl treatment in microglia, but increased in astrocytes. LPS, which served as a positive control, strongly increased cytokine mRNA expression (Fig. 5) and prostanoid synthesis (Fig. 4) in both cell types. As shown by immunofluorescence (Fig. 6A) and western blot analysis (Fig. 6B,C), intraperitoneal injection of ammonium acetate (4.5 mmol/kg) increased Iba-1 expression in the cerebral cortex within 6 hours, suggestive for in vivo microglia activation after ammonia intoxication.

A recently published randomized, double-blind, placebo-controlled trial in chronic pancreatitis patients has shown the significant therapeutic efficacy of these modern enzyme preparations

in reducing fat excretion, decreasing stool frequency and improving stool consistency.16 These results have been confirmed by means of the 13C-MTG breath test, analysis of coefficient of fat absorption and nutritional status in a recent prospective study including 49 patients with fat maldigestion secondary to chronic pancreatitis.6 Similar efficacy was shown in a placebo-controlled trial in patients suffering from cystic fibrosis with pancreatic exocrine insufficiency and steatorrhea.17 Despite the use of modern enteric-coated enzyme preparations in minimicrospheres,

fat digestion cannot revert to normal in almost half of the patients with pancreatic exocrine insufficiency.18 Inadequate patient compliance, low dose selleck chemicals of enzymes, acidic intestinal pH and intestinal bacterial overgrowth are among the factors hampering total elimination of steatorrhea in this clinical setting.19 Patient compliance is a key factor in the management of pancreatic exocrine insufficiency with oral pancreatic enzymes. Patients should understand the importance of the therapy and the correct administration schedule.15 In addition, the prescribed dose of enzymes should be high enough, and a minimum dose of 40 000–50 000 Eur. Lumacaftor Ph. U of lipase per meal is required.7,8 Phospholipase D1 The abnormally low pancreatic

secretion of bicarbonate in patients with pancreatic exocrine insufficiency is associated with a limited buffering effect in the proximal intestine. A pH below 4 is associated with an irreversible inactivation of endogenous and uncoated exogenous pancreatic lipase, as well as with precipitation of bile salts, contributing to fat maldigestion.20 In addition, enteric-coated pancreatic enzymes require a pH > 5 to be released, which may first occur in distal segments of the small intestine, thus reducing the efficacy of the therapy.21 Up to 40% of patients with pancreatic exocrine insufficiency secondary to chronic pancreatitis have concomitant intestinal bacterial overgrowth.22 This is probably due to a defect in the interdigestive “house keeper” function of gastrointestinal motility and biliopancreatic secretion. In fact, patients with chronic pancreatitis have been shown to lose the physiological synchrony between the interdigestive gastrointestinal motility and pancreatic secretion. These, together with a markedly low pancreatic secretion of enzymes, may favor the development of bacterial overgrowth.23 The first step to guarantee an optimal efficacy of oral pancreatic enzymes in the management of pancreatic exocrine insufficiency is to confirm the proper use of enzymes by patients.

The decline/decrease in these mutants was completely blocked/restored by a potent proteasome inhibitor, MG-132. This was consistent with the prediction by molecular modelling that

the mutant molecules would lose the native structure of wild-type molecule, leading to their instability and degeneration and ultimately to degradation. These mutants might have significantly altered conformations, resulting in the rapid degradation by the proteasome inside the synthesizing cells, and ultimately leading to FXIII deficiency. “
“A number of studies have been published on the benefits of prophylactic treatment in adults with haemophilia. However, in many countries, it is considered as optional due to financial constraints. GS-1101 mouse This survey was carried out to examine the long-term effects of prophylaxis and the continuing benefit of the treatment into adulthood. Self-assessed health-related data and the EQ-5D questionnaire measuring health utility were collected from 124 men (26.9 ± 4.6 years) from Canada (N = 40), France (N = 14), Ireland (N = 17), the Netherlands (N = 16), Poland (N = 24) and the UK (N = 13). The respondents were split into four groups: On-Demand, <50% life selleck chemicals on prophylaxis, ≥50% life

on prophylaxis, Prophylaxis. Overall, long-term prophylaxis results in lower presence of target joints (P ≤ 0.001), occurrence of serious bleeding episodes (P ≤ 0.05), recurring bleeding episodes (P ≤ 0.01) and requirement for surgical procedures (P ≤ 0.05). Furthermore, health utility (P ≤ 0.01) in the On-demand group was significantly lower (P ≤ 0.01) compared to the ≥50% life on prophylaxis and the Prophylaxis

group. No significant differences between countries were found except between the Netherlands and Poland, with Poland showing the lowest health utility (P ≤ 0.01) and the most problems with mobility (P ≤ 0.05) and pain/discomfort (P ≤ 0.001). The Netherlands showed the highest health utility (0.915) followed by Canada (0.791), Ireland (0.786), UK (0.768), France (0.687) and Poland (0.629). The results demonstrate consistently higher quality of life of individuals who are on long-term prophylactic treatment when compared to on-demand treatment or intermittent prophylaxis and on -demand treatment. In haemophilia, prophylaxis for children with severe FVIII and FIX deficiencies Mirabegron is recognized as the optimum standard of care [1-3]. However, the continuation of prophylactic therapy into adulthood is still closely scrutinized. In many countries, the clinical benefit is acknowledged, although given the limited resources not everywhere provides prophylaxis into adulthood. A number of studies have been published demonstrating the benefits of prophylactic treatment in adults [4-6]. This study was carried out to examine the long-term effects of prophylaxis and the continuing benefit of the therapy into adulthood. It is an expansion of the four-country survey reported in 2009 [7].

14 HepG2 cells were cultured in Roswell Park Memorial Institute 1640 medium (RPMI), Hep3B cells were cultured in minimal essential medium (MEM), and HuH7, PLC/PRF/5, and AKN1 cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) (all media were obtained from PAA Laboratories, Cölbe, Germany) supplemented with 10% fetal calf serum and 1% penicillin/streptomycin (Sigma, selleck compound St. Louis, MO) in an atmosphere containing 5% CO2. High-molecular weight DNA was isolated from fresh-frozen NL, CL, DN, and HCC tissue samples and cultured cells using the DNeasy Blood and Tissue Kit (Qiagen, Hilden, Germany). DNA from formalin-fixed

paraffin-embedded (FFPE) tissue was isolated using the QIAamp DNA FFPE Tissue kit (Qiagen) with an additional 16 hours proteinase K digestion. Genomic DNA was converted by bisulfite treatment

using the EZ DNA methylation kit (Zymo Research, Orange, CA). Fresh-frozen tissue samples included 16 HCC, six CL, six microdissected CL (CL microdissected), 17 NL, and five human liver tumor cell lines. DN were obtained from 11 FFPE tissue specimens. Regions for quantitative DNA methylation analysis covered the CpG islands around the respective transcription start sites of the two AKAP12 isoforms α and β (Fig. 1) and were targeted by amplicons of up to 460 bp in size Daporinad (see Supporting Table 4). In total, our analysis covered 44% of the genomic CpG sites of the AKAP12α promoter and 41% of genomic CpG

sites of AKAP12β promoter. The amplicons A1 and A2, and B1 were the most representative genomic regions of all analyzed amplicons in both isoforms for depicting methylation differences between normal, preneoplastic, and neoplastic tissue (data not shown). Smaller amplicons which were located in those most informative regions were used to characterize methylation levels of FFPE DN samples. Bisulfite-converted DNA was polymerase chain reaction (PCR) amplified, in vitro transcribed, base-specifically cleaved by RNase A, and subjected to matrix-assisted laser desorption, ionization-time-of-flight mass spectrometry (MassARRAY technique; Sequenom, San Diego, CA) as described.15 DNA methylation standards (0%, Diflunisal 20%, 40%, 60%, 80%, and 100% methylated genomic DNA) were used for data correction. To assure that the methylation analysis of CL samples was not contaminated by nonparenchymal cells, microdissection was performed. CL tissue samples were cut into 18-μm-thick sections using a cryostat (Leica CM1850; Leica Microsystems, Wetzlar, Germany) and laser microdissection was performed as described.16 Human HCC cell lines (AKN1, HepG2, and HuH7) were incubated for 72 hours with 10 μmol/L 5-aza-dC (Sigma-Aldrich, St. Louis, MO) with a medium change every 24 hours. Genomic DNA was isolated from treated cells as described and total RNA was purified using Trizol reagent (Invitrogen, Karlsruhe, Germany).

This effect is mediated by up-regulation of specific genes related to a myo/contractile phenotype. After transdifferentiation, PF-6463922 research buy PTFs expressed α-smooth muscle actin (α-SMA) and enhanced proliferation, migration, and invasion of HCC cells occur. A pan-LPA inhibitor (α-bromomethylene phosphonate [BrP]-LPA), or autotaxin gene silencing, inhibited this PTF transdifferentiation and the consequent enhanced proliferation, migration, and invasion of HCC cells. In vivo, PTFs coinjected with HCC cells underwent transdifferentiation and promoted tumor progression. Treatment with BrP-LPA blocked transdifferentiation of PTFs, down-regulated

myofibroblast-related genes, and slowed HCC growth and progression. Patients with larger and metastatic HCC and shorter survival displayed higher serum levels of LPA. Analysis of microdissected tissues indicated that stroma is the main target of the LPA paracrine loop in HCC. As a consequence, α-SMA–positive cells were more widespread in tumoral compared with paired peritumoral stroma. Conclusion:

Our data indicate that LPA accelerates HCC progression by recruiting PTFs and promoting their transdifferentiation into myofibroblasts. Inhibition of LPA could prove effective in blocking transdifferentiation of myofibroblasts and tumor progression. (HEPATOLOGY 2011;) In Western Rapamycin countries, hepatocellular carcinoma (HCC) develops in patients with liver cirrhosis and is the final stage of a disease that can last Tau-protein kinase for many years.1, 2 It is generally accepted that HCC originates from hepatocytes but grows and advances while fully embedded in a surrounding microenvironment with a rich content of myofibroblasts, fibroblasts, and other cell

types due to the underlying cirrhosis. Liver myofibroblasts, derived from quiescent fibroblasts and hepatic stellate cells activated by the chronic injury, can be recognized by their expression of α-smooth muscle actin (α-SMA).3, 4 Myofibroblasts have been detected at the advancing edge of several different malignancies as the predominant phenotype in the cancer-associated fibroblast (CAF) population.5 Although the origin of CAFs is still controversial, their immunophenotypical characterization, which primarily includes α-SMA and excludes epithelial and endothelial common markers, is widely accepted.3, 6, 7 CAFs differ from peritumoral tissue fibroblasts (PTFs) not in terms of somatic mutations but rather molecular and functional differences in modulating neighboring cancer cells.8, 9 However, the paracrine cross-talk between HCC and stromal fibroblasts such as CAFs or PTFs is still poorly understood. HCC is recognized as a highly heterogeneous tumor because of its complex multistep pathogenesis, which is further complicated by the preexisting liver cirrhosis. For this reason, the identification of a proper biological target is essential in order to design suitable molecular-oriented therapy.

Our data also suggest that the inflammatory pathway is not involved in hepcidin regulation by iron. In summary, our results demonstrate that circulating iron and tissue iron differentially activate the BMP-SMAD signaling pathway to modulate hepcidin expression. The liver is the predominant source of

the BMP6 that regulates hepcidin in response to iron in vivo, and increases in LIC induce hepatic expression of BMP6 ligand, whereas increases in Tf sat activate SMAD1/5/8 phosphorylation downstream of BMP6. Inhibitory SMAD7 is significantly modulated by both acute and chronic iron administration, mirroring the overall activation of the SMAD1/5/8 signaling cascade, and may play a role Selleck Small molecule library in feedback inhibition of hepcidin expression. Hepatic Erk1/2 phosphorylation is not stimulated by either acute or chronic Daporinad solubility dmso iron administration in mice, suggesting that these MAP kinases are not involved in hepcidin regulation by iron in vivo. Future studies will be needed to further delineate the

precise molecular mechanisms involved in iron sensing and BMP6-SMAD pathway activation in hepcidin regulation and iron homeostasis. Additional Supporting Information may be found in the online version of this article. “
“Acute-on-chronic liver failure (ACLF) is a clinical entity where there is a potential for reversibility of hepatic dysfunction once the acute hepatic insult resolves. The portal and systemic hemodynamics Benzatropine in ACLF patients to study its relevance in determining the clinical outcomes was studied. Clinical, laboratory, portal, and systemic hemodynamic assessments were done at admission and after 3 months. Standard medical care was given to all the patients. Fifty-seven patients with ACLF were enrolled, and they underwent baseline hepatic venous pressure gradient (HVPG) measurement. Twenty-six (46%) patients died during the 3-month follow-up.

Presence of high HVPG and hepatic encephalopathy were found to be independent baseline predictors of mortality. Of the 31 surviving patients, 24 consented for a repeat HVPG. The baseline HVPG reduced from 16 (range 12–30) to 13 (range 6–21) mmHg; (P < 0.05). The reduction in HVPG correlated with clinical and biochemical recovery, and reduction in Child–Turcotte–Pugh score score (P < 0.05), while the aortic mean arterial pressure, cardiac index and systemic vascular resistance index improved significantly (< 0.05). Six (25%) patients developed upper gastrointestinal bleed; the median HVPG between bleeders and non-bleeders was not different possibly because of early onset of bleed (median 20 [15–45 days]). Baseline HVPG is an independent predictor of mortality in ACLF patients. The portal and systemic circulatory anomalies regress substantially by 90 days and correlate with clinical recovery.

4). To test whether continuous NF-κB activation is needed for the observed changes, we compared gene expression in 4-week-old mice with sustained NF-κB activation with animals Crizotinib clinical trial where CAIKK2 expression was inhibited for 3 days by DOX readministration. DOX readministration for 3 days inhibited CAIKK2 expression

(Fig. 5A). Histological analyses revealed that the livers from DOX-readministered mice exhibited less inflammation (Desmet score: control 0, CAIKK2LAP 0.8 ± 0.5) compared to those from mice without DOX readministration (Desmet score: control 0, CAIKK2LAP 2.5 ± 0.8, P = 6 × 10−3) (Fig. 5B,C). Expression of stress response genes and chemokines was reversed in DOX-treated animals, suggesting that these processes require

continuous NF-κB activation (Fig. 5D). Furthermore, 12-week-old animals were readministered DOX for 3 weeks. Histological analyses, as well as hydroxyproline assay, revealed that despite the NF-κB system being switched off, hepatic fibrosis did not regress within this time frame (Supporting Fig. S5). Although 3 weeks might have been too short to significantly reduce the extent of liver fibrosis, HSC activation markers were all down-regulated after readministration of DOX (Fig. 5E), suggesting that activation of HSCs is dependent on buy Sirolimus sustained activation of the hepatic NF-κB system. Given the increased presence of macrophage surface markers as well as genes involved in macrophage activation in our microarray analysis (Fig. 4D), we hypothesized that activation of hepatocellular NF-κB signaling leads to liver fibrosis development by way of macrophage recruitment. To test whether hepatocyte-mediated recruitment of macrophages contributes to liver fibrogenesis, we injected clodronate liposomes, an established macrophage-depleting agent. Injection of clodronate liposomes from age 3 to 12 weeks resulted in a marked decrease in macrophage surface marker F4/80, as well as attenuated lysozyme

M and Cxcl10 expression, whereas CAIKK2 expression was intact (Fig. 6A,B; Supporting Fig. S6B). Unaltered levels of F4/80 expression were observed in animals injected with control liposomes (Fig. click here 6B). Clodronate administration did not reduce the extent of hepatic damage (Supporting Fig. S6A), or the extent of overall inflammation as suggested by unaltered levels of several inflammation-related genes (Supporting Fig. S6B). On the other hand, we observed attenuated fibrogenesis as evidenced by Sirius-red staining (Fig. 6C) and by Desmet scoring (Fig. 6D). A reduction of collagen deposition was also confirmed by hydroxyproline assay and morphometrical analysis of Sirius-red-stained sections (Fig. 6C,E). Thus, our data indicate that sustained hepatocellular NF-κB activation leads to liver fibrosis development by way of recruitment and activation of macrophages.

The same

finding was reported by Rosenberg et al[15] for implants with hydroxyapatite surface enhanced by patients’ conditions (periodontally compromised). This may be due to ease of microbial adhesion to rough compared to the machined surface. Teughels et al[24] conducted a systematic review of the literature on the effect of material characteristics and/or surface topography of the implant in the development of the biofilm (plaque), concluding that implant surfaces with a higher find more degree of roughness (R = 0.2 μm) facilitate biofilm formation. In a retrospective evaluation of predisposing conditions for the occurrence of retrograde peri-implant pathology in Brånemark system implants, Quirynen et al[12] observed a higher incidence of retrograde peri-implant pathology in TiUnite (rough) (Nobel Biocare) implants. The components of an implant-prosthetic rehabilitation (abutment, abutment screw, and crown/prosthesis)

may relate to the occurrence of peri-implant pathology, to the extent that they are part of the equation when the disease occurs by occlusal overload.[25] Regarding the abutments, there is no evidence that the different surface topography influences the accumulation of plaque either in the animal model[26] or in a human model as evidenced by Van Assche et al[27] through GSK-3 inhibitor a randomized clinical trial comparing the accumulation of plaque on different surfaces. Regarding the type of prosthetic reconstruction, a higher incidence of implant failures and prosthetic complications have been observed in partially edentulous patients rehabilitated with a fixed partial prosthesis supported by two implants compared to a prosthesis supported by three or more implants.[28-30] This may occur due to a biomechanically unfavorable situation with respect to the number of implants supporting the structure.[31] The type of restorative material used in the prosthesis ranges from acrylic, metal-acrylic, metal-ceramic, and to ceramic. The academic hypothesis of using acrylic as a means

of reducing the concentration of occlusal stress on the bone/implant interface[32] Avelestat (AZD9668) acting as a shock absorbing agent has been postulated; this assumption is supported by finite element analysis studies and mathematical models.[33, 34] However, there were no significant differences in marginal bone loss between implants restored with ceramic or acrylic in clinical studies.[35] The presence of cantilevers in a fixed prosthesis has been considered a risk factor due to the considerable increase of occlusal load on the implants, especially the most distal implant.[32] These results have been supported by in vitro studies,[36-38] suggesting a maximum limit of a 15-mm-long cantilever in the mandible.[38] A recent meta-analysis from retrospective cohort studies concluded that there were no differences in bone loss in implants supporting a cantilever because of this factor per se.

With the development of cyclo-oxygenase 2 (COX-2) specific inhibitors, safe anti-inflammatory agents were claimed to be available for patients with a history of peptic ulcer disease to prevent complications. While COX-2 inhibitors might

be safe for average risk patients, a randomized study showed that in patients who had a history of peptic ulcer bleeding, celecoxib usage led to recurrent bleeding in 4.9% and conventional NSAID B-Raf inhibitor drug (diclofenac) combined with proton pump inhibitor (omeprazole) in 6.4% in a period of 6 months.30 These are not negligible risks of recurrent bleeding and therefore a more safe approach needs to be sorted. We tested the combination of COX-2 inhibitor with proton pump inhibitor and compared against COX-2 inhibitor alone in a group of high-risk patients who required an anti-inflammatory agent for arthritis.31 In a study enrolling 441 patients, the combination of COX-2 inhibitor and proton pump inhibitor (PPI) was found to be associated with significantly fewer re-bleeding episodes than COX-2 inhibitor alone (0% vs 8.9%). This finding should encourage the recommendation of combination therapy in very high risk patients who require anti-inflammatory www.selleckchem.com/products/Romidepsin-FK228.html therapy. However, the increased cardiovascular risk in long-term use of COX-2 inhibitors should lead to caution against its usage in patients with coronary heart disease. A balance between the gastrointestinal risk and cardiovascular risk should be evaluated in patients

who require long-term anti-inflammatory therapy. Table 1 is a suggested permutation for clinicians’ reference. Aspirin is well known to have ulcerogenic effects and the magnitude of GI toxicity is comparable to conventional NSAIDs. However, with the increasing incidence of cardiovascular and cerebrovascular disease worldwide, the consumption of aspirin and other anti-platelet agents is ever increasing. Unlike conventional NSAIDs, before prescribing low-dose aspirin to patients with history of peptic ulcer disease, eradication of H. pylori infection confers significant

protection against peptic ulcer and ulcer complications. In a randomized study comparing anti-Helicobacter therapy against proton pump inhibitors in patients with a history of Adenosine peptic ulcer bleeding, the two strategies had comparable clinical outcomes over 6 months.29 This is a distinctly different phenomenon compared with conventional NSAIDs (see above). Therefore, checking for H. pylori infection and treating when testing positive for this infection is very important among aspirin users. In recent years, clopidogrel and other anti-platelet agents have been developed to provide safer drugs for GI protection. Clopidogrel, being the prototype of these agents, has been widely used either singularly or in combination with aspirin in patients with coronary heart disease and stroke. When used in high-risk patients, however, clopidogrel is not as safe as claimed to be in the gastrointestinal tract.

However, the recent work of Treiber et al. (2012) that questions the structure and location of magnetoreceptors could actually be viewed as a strength and sign of health: of a field that welcomes new results that may force revisions of current models of understanding. While many aspects of navigation are unresolved, as this review indicates, that does not mean that

there is no data. While the models for studying navigation are imperfect, closer links between laboratory work and field work are being established, and the addition of new technology for studying animals in the wild will broadened our understanding of the behaviour of migrating birds and the challenges they face (Guilford et al., 2011). The integration of neurobiology, Ensartinib supplier physics and molecular biology into the discipline is now well established and has led to a number of breakthroughs in our understanding of the magnetic sense as well as TGF-beta inhibitor the role of the olfactory sense in navigation. The integration of these disciplines

has led to testable predictions about the structure of sensory systems and potentially the mechanisms of navigation. For the field to advance further, the link between these disciplines and behavioural biology needs to strengthen further, in order to reduce the ‘black box’ understanding of some of the systems involved. For example, a better knowledge of the structure of the ferromagnetic sense will allow better predictions

about the effect of magnetic pulse treatments to understand how receptors are changed by the treatment. Strengthening this integration of other disciplines, while maintaining the roots as a behavioural biology discipline, will ultimately lead to the solution of the ‘mystery’ of bird navigation. I will finish this review by highlighting some of the key issues that should be resolved in order for the field of true navigation in migratory birds to advance. (1)  Is the true navigation map unimodal, that is one environmental cue provides all information on location, bimodal, 5-Fluoracil that is two separate environmental cues provide different aspects of the location (e.g. latitude and longitude), or redundant, that is do multiple cues provide the same information for different aspects of the location. Solving this will help to understand some of the inconsistencies and conflicting evidence in the field, as it will establish whether failure to repeat is a consequence of experimental design rather than redundancy of cues. I thank John Phillips and two anonymous reviewers for helpful comments on the paper. Aspects of this review also came as a result of enjoyable discussions with the Navigation Special Interest Group at the MIGRATE NSF funded meeting in Konstanz, 2010 with Susanna Åkesson, Verner Bingman, Tim Guilford, Anna Gagliardo, Henrik Mouritsen, Rachel Muheim, Rosie Wiltschko and Wolfgang Wiltschko.